Brief communication: New method for measuring nitrogen isotopes in tooth dentine at high temporal resolution.

OBJECTIVES: Nitrogen isotopes (δ15N) are widely used to study human nursing and weaning ages. Conventional methods involve sampling 1-mm thick sections of tooth dentine-producing an averaging effect that integrates months of formation. We introduce a novel protocol for measuring δ15N by multicollector secondary ion mass spectrometry (SIMS). MATERIALS AND METHODS: We sampled dentine δ15N on a weekly to monthly basis along the developmental axis in two first molars of healthy children from Australia and New Zealand (n = 217 measurements). Nitrogen isotope ratios were determined from measurements of CN- secondary molecular ions in ~35 µm spots. By relating spot position to enamel formation, we identified prenatal dentine, as well as sampling ages over more than 3 years. We also created calcium-normalized barium and strontium maps with laser ablation-inductively coupled plasma-mass spectrometry. RESULTS: We found rapid postnatal δ15N increases of ~2‰-3‰, during which time the children were exclusively breastfed, followed by declines as the breastfeeding frequency decreased. After weaning, δ15N values remained stable for several months, coinciding with diets that did not include meat or cow's milk; values then varied by ~2‰ starting in the third year of life. Barium did not show an immediate postnatal increase, rising after a few months until ~1-1.5 years of age, and falling until or shortly after the cessation of suckling. Initial strontium trends varied but both individuals peaked months after weaning. DISCUSSION: Developmentally informed SIMS measurements of δ15N minimize time averaging and can be precisely related to an individual's early dietary history.

Associations between prenatal metal and metalloid mixtures in teeth and reductions in childhood lung function.

BACKGROUND: Metal(oid)s have been cross-sectionally associated with lung function outcomes in childhood but there is limited data on their combined effects starting in utero. Child sex may further modify these effects. OBJECTIVE: Examine associations between in utero and early life exposure to metals assessed via novel dentine biomarkers and childhood lung function and explore effect modification by child sex. METHODS: Analyses included 291 children enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, a longitudinal birth cohort study in Mexico City. Weekly dentine levels of arsenic (As), cadmium (Cd), cobalt (Co), copper (Cu), manganese (Mn), nickel (Ni), and lead (Pb) were measured from 15 weeks pre-birth to 15 weeks post birth in deciduous children's teeth. Lung function was tested at ages 8-14 years and then modeled as age, height and sex adjusted z-scores. Associations were modeled using lagged weighted quantile sum (LWQS) regression to evaluate the potential for a time-varying mixture effect adjusting for maternal age and education at enrollment and exposure to environmental tobacco smoke in pregnancy. Models were also stratified by sex. RESULTS: We identified a window of susceptibility at 12-15 weeks pre-birth in which the metal mixture was associated with lower FVC z-scores in children aged 8-14 years. Cd and Mn were the largest contributors to the mixture effect (70 %). There was also some evidence of effect modification by sex, in which the mean weights and weighted correlations over the identified window was more evident in males when compared to females. In the male stratum, Cd, Mn and additionally Pb also dominated the mixture association. CONCLUSIONS: Prenatal metal(oid) exposure was associated with lower lung function in childhood. These findings underscore the need to consider both mixtures and windows of susceptibility to fully elucidate effects of prenatal metal(oid) exposure on childhood lung function.

Detection and Imaging of Exposure-Related Metabolites and Xenobiotics in Hard Tissues by Laser Sampling and Mass Spectrometry.

The utility of two novel laser-based methods, laser ablation electrospray ionization (LAESI) and laser desorption ionization (LDI) from silicon nanopost array (NAPA), is explored via local analysis and mass spectrometry imaging (MSI) of hard tissues (tooth and hair) for the detection and mapping of organic components. Complex mass spectra are recorded in local analysis mode from tooth dentin and scalp hair samples. Nicotine and its metabolites (cotinine, hydroxycotinine, norcotinine, and nicotine) are detected by LAESI-MS in the teeth of rats exposed to tobacco smoke. The intensities of the detected metabolite peaks are proportional to the degree of exposure. Incorporating ion mobility separation in the LAESI-MS analysis of scalp hair enables the detection of cotinine in smoker hair along with other common molecular species, including endogenous steroid hormones and some lipids. Single hair strands are imaged by MALDI-MSI and NAPA-LDI-MSI to explore longitudinal variations in the level of small molecules. Comparing spectra integrated from NAPA-LDI-MSI and MALDI-MSI images reveals that the two techniques provide complementary information. There were 105 and 82 sample-related peaks for MALDI and NAPA, respectively, with an overlap of only 16 peaks, indicating a high degree of complementarity. Enhanced molecular coverage and spatial resolution offered by LAESI-MS and NAPA-LDI-MSI can reveal the distributions of known and potential biomarkers in hard tissues, facilitating exposome research.

Oxygen isotopes in orangutan teeth reveal recent and ancient climate variation.

Studies of climate variation commonly rely on chemical and isotopic changes recorded in sequentially produced growth layers, such as in corals, shells, and tree rings, as well as in accretionary deposits-ice and sediment cores, and speleothems. Oxygen isotopic compositions (δ18O) of tooth enamel are a direct method of reconstructing environmental variation experienced by an individual animal. Here, we utilize long-forming orangutan dentitions (Pongo spp.) to probe recent and ancient rainfall trends on a weekly basis over ~3-11 years per individual. We first demonstrate the lack of any consistent isotopic enrichment effect during exclusive nursing, supporting the use of primate first molar teeth as environmental proxies. Comparisons of δ18O values (n=2016) in twelve molars from six modern Bornean and Sumatran orangutans reveal a high degree of overlap, with more consistent annual and bimodal rainfall patterns in the Sumatran individuals. Comparisons with fossil orangutan δ18O values (n=955 measurements from six molars) reveal similarities between modern and late Pleistocene fossil Sumatran individuals, but differences between modern and late Pleistocene/early Holocene Bornean orangutans. These suggest drier and more open environments with reduced monsoon intensity during this earlier period in northern Borneo, consistent with other Niah Caves studies and long-term speleothem δ18O records in the broader region. This approach can be extended to test hypotheses about the paleoenvironments that early humans encountered in southeast Asia.

When an animal drinks water, two naturally occurring variants of oxygen ­ known as oxygen-18 and oxygen-16 ­ are incorporated into its growing teeth. The ratio of these variants in water changes with temperature, rainfall and other environmental conditions and therefore can provide a record of the climate during an animal's life. Teeth tend to be well preserved as fossils, which makes it possible to gain insights into this climate record even millions of years after an animal's death. Orangutans are highly endangered great apes that today live in rainforests on the islands of Borneo and Sumatra. During a period of time known as the Pleistocene (around 2.6 million years to 12,000 years ago), these apes were more widely spread across Southeast Asia. Climate records from this area in the time before human-induced climate change are somewhat limited. Therefore, fossilized orangutan teeth offer a possible way to investigate past seasonal rainfall patterns and gain insight into the kind of environments early humans would have encountered. To address this question, Smith et al. measured oxygen-18 and oxygen-16 variants in thin slices of modern-day orangutan teeth using a specialized analytical system. This established that the teeth showed seasonal patterns consistent with recent rainfall trends, and that the ratio of these oxygen variants did not appear to be impacted by milk intake in young orangutans. These findings indicated that the oxygen variants could be a useful proxy for predicting prehistoric weather patterns from orangutan teeth. Further measurements of teeth from fossilized Sumatran orangutans showed broadly similar rainfall patterns to those of teeth from modern-day orangutans. On the other hand, fossilized teeth from Borneo suggested that the environment used to be drier, with less intense wet seasons. The approach developed by Smith et al. provides an opportunity for scientists to leverage new fossil discoveries as well as existing collections to investigate past environments. This could allow future research into how climate variation may have influenced the spread of early humans through the region, as well as the evolution of orangutans and other endangered animals.

Early-life manganese exposure during multiple developmental periods and adolescent verbal learning and memory.

BACKGROUND: Manganese (Mn) is both an essential and toxic metal, and associations with neurodevelopment depend on exposure timing. Prospective data examining early life Mn with adolescent cognition are sparse. METHODS: We enrolled 140 Italian adolescents (10-14 years old) from the Public Health Impact of Metals Exposure study. Mn in deciduous teeth was measured using laser ablation-mass spectrometry to represent prenatal, postnatal and early childhood exposure. The California Verbal Learning Test for Children (CVLT-C) was administered to assess adolescent verbal learning and memory. Multivariable regression models estimated changes in CVLT-C scores and the odds of making an error per doubling in dentine Mn in each exposure period. Multiple informant models tested for differences in associations across exposure periods. RESULTS: A doubling in prenatal dentine Mn levels was associated with lower odds of making an intrusion error (OR = 0.23 [95% CI: 0.09, 0.61]). This beneficial association was not observed in other exposure periods. A doubling in childhood Mn was beneficially associated with short delay free recall: (ß = 0.47 [95% CI: -0.02, 0.97]), which was stronger in males (ß = 0.94 [95% CI: 0.05, 1.82]). Associations were null in the postnatal period. CONCLUSION: Exposure timing is critical for understanding Mn-associated changes in cognitive function.

Early-Life Critical Windows of Susceptibility to Manganese Exposure and Sex-Specific Changes in Brain Connectivity in Late Adolescence.

Background: Early-life environmental exposures during critical windows (CWs) of development can impact life course health. Exposure to neuroactive metals such as manganese (Mn) during prenatal and early postnatal CWs may disrupt typical brain development, leading to persistent behavioral changes. Males and females may be differentially vulnerable to Mn, presenting distinctive CWs to Mn exposure. Methods: We used magnetic resonance imaging to investigate sex-specific associations between early-life Mn uptake and intrinsic functional connectivity in adolescence. A total of 71 participants (15-23 years old; 53% female) from the Public Health Impact of Manganese Exposure study completed a resting-state functional magnetic resonance imaging scan. We estimated dentine Mn concentrations at prenatal, postnatal, and early childhood periods using laser ablation-inductively coupled plasma-mass spectrometry. We performed seed-based correlation analyses to investigate the moderating effect of sex on the associations between Mn and intrinsic functional connectivity adjusting for age and socioeconomic status. Results: We identified significant sex-specific associations between dentine Mn at all time points and intrinsic functional connectivity in brain regions involved in cognitive and motor function: 1) prenatal: dorsal striatum, occipital/frontal lobes, and middle frontal gyrus; 2) postnatal: right putamen and cerebellum; and 3) early childhood: putamen and occipital, frontal, and temporal lobes. Network associations differed depending on exposure timing, suggesting that different brain networks may present distinctive CWs to Mn. Conclusions: These findings suggest that the developing brain is vulnerable to Mn exposure, with effects lasting through late adolescence, and that females and males are not equally vulnerable to these effects. Future studies should investigate cognitive and motor outcomes related to these associations.

Brief Communication: Elemental Models of Primate Nursing and Weaning Revisited.

Objectives: Intra-tooth patterns of trace elements barium (Ba) and strontium (Sr) have been used to infer human and nonhuman primate nursing histories, including australopithecine and Neanderthal juveniles. Here we contrast the two elemental models in first molars (M1s) of four wild baboons and explore the assumptions that underlie each. Materials and Methods: Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was employed to create comprehensive calcium-normalized barium and strontium (Ba/Ca, Sr/Ca) maps of M1 enamel and dentine at 35 micron resolution. Results: Postnatal Ba/Ca values were typically high, peaking ~0.5 years of age and then decreasing throughout M1 crown formation; all four individuals showed minimal Ba/Ca values between ~1.2-1.8 years, consistent with field reports of the cessation of suckling. Enamel Sr/Ca did not support patterns of previous LA-ICP-MS spot sampling as the enamel rarely showed discrete Sr/Ca secretory zonation. Increases in Sr/Ca appeared in coronal dentine beginning ~0.3 years, with varied peak value ages (~0.7-2.7 years) and no evidence of a predicted postweaning decline. Discussion: Inferences of baboon weaning ages from initial Ba/Ca minima are more congruent with behavioral observations than Sr/Ca maxima; this is consistent with studies of captive macaques of known weaning ages. Elemental variation is more apparent in the coronal dentine than the enamel of these baboons, which may relate to its more rapid mineralization and protection from the oral environment. Inferences of nursing histories from enamel Sr/Ca patterns alone should be reconsidered, and elevated values of Ba/Ca and Sr/Ca in teeth formed after weaning require further study.

Microspatial distribution of trace elements in feline dental hard tissues: early life exposure to essential and toxic elements.

Introduction: Trace elements play a key role in dental tissue development, as dental hard tissues accumulate both essential and toxic trace elements during mineralization. Characterization of the spatial accumulation pattern of trace elements may provide insight into exposure to toxic elements over time and to the nature of disease processes affecting the hard dental tissues. Here, we present the first report of the use of laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to map the microspatial distribution of multiple trace elements, essential and toxic, across feline dental hard tissues. Methods: Eleven teeth were extracted from 8 cats. Nine teeth were from 7 cats diagnosed with idiopathic tooth resorption on intraoral radiographs prior to extraction. Two teeth were included from a cadaver that had no signs of tooth resorption on intraoral radiographs. The normal dental tissue was analyzed from each sample using LA-ICP-MS to map the microspatial distribution of essential and toxic trace elements across feline enamel, dentin, and cementum. Results: Results showed a higher accumulation of barium and strontium in coronal dentin as compared to root dentin. The timing of the accumulation mirrors nursing timelines seen in teeth from human and non-human primates, consistent with barium and strontium being sourced from maternal milk. Results also showed a higher uptake of lead in the coronal dentin, suggesting this lead exposure was likely passed from mother to offspring. Discussion: This work characterizes a baseline for elemental distribution in feline teeth linked to early life exposure to toxic elements such as lead and provides a framework for future studies investigating long-term environmental exposures to trace elements, essential and toxic, and their involvement in feline systemic and dental diseases.

Stress exposure histories revealed by biochemical changes along accentuated lines in teeth.

The regular incremental secretion of enamel and dentine can be interrupted during periods of stress resulting in accentuated growth lines. These accentuated lines, visible under light microscopy, provide a chronology of an individual's stress exposure. Previously, we showed that small biochemical changes along accentuated growth lines detected by Raman spectroscopy, coincided with the timing of medical history events and disruptions of weight trajectory in teeth from captive macaques. Here, we translate those techniques to study biochemical changes related to illness and prolonged medical treatment during early infancy in humans. Chemometric analysis revealed biochemical changes related to known stress-induced changes in circulating phenylalanine as well as other biomolecules. Changes in phenylalanine are also known to affect biomineralization which is reflected in changes in the wavenumbers of hydroxyapatite phosphate bands associated with stress in the crystal lattice. Raman spectroscopy mapping of teeth is an objective, minimally-destructive technique that can aid in the reconstruction of an individual's stress response history and provide important information on the mixture of circulating biochemicals associated with medical conditions, as applied in epidemiological and clinical samples.

Deciduous tooth biomarkers reveal atypical fetal inflammatory regulation in autism spectrum disorder.

Atypical regulation of inflammation has been proposed in the etiology of autism spectrum disorder (ASD); however, measuring the temporal profile of fetal inflammation associated with future ASD diagnosis has not been possible. Here, we present a method to generate approximately daily profiles of prenatal and early childhood inflammation as measured by developmentally archived C-reactive protein (CRP) in incremental layers of deciduous tooth dentin. In our discovery population, a group of Swedish twins, we found heightened inflammation in the third trimester in children with future ASD diagnosis relative to controls (n = 66; 14 ASD cases; critical window: -90 to -50 days before birth). In our replication study, in the US, we observed a similar increase in CRP in ASD cases during the third trimester (n = 47; 23 ASD cases; -128 to -21 days before birth). Our results indicate that the third trimester is a critical period of atypical fetal inflammatory regulation in ASD.

Equine odontoclastic tooth resorption and hypercementosis (EOTRH): microspatial distribution of trace elements in hypercementosis-affected and unaffected hard dental tissues.

Equine Odontoclastic Tooth Resorption and Hypercementosis (EOTRH) is a common, painful and poorly understood disease. Enamel, dentin and cementum accumulate both essential and toxic trace elements during mineralization. Characterization of the spatial accumulation pattern of trace elements may provide insight into the role that toxic elements play and inform biological processes affecting these hard dental tissues for future research. Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was used to map the distribution of multiple trace elements and heavy metals across equine healthy and diseased (hypercementosis-affected) hard dental tissues among four teeth extracted from horses with EOTRH. Results showed banding patterns of some trace elements (lead, strontium, barium), reflecting the temporal component of accumulation of trace elements during dentin mineralization. Essential elements zinc and magnesium did not show banding patterns. Comparison to the unaffected cementum and dentin adjacent to the hypercementosis region showed that there is an underlying incremental pattern in the uptake of some metals with spatial irregularities. This supports a possible metabolic change involved in hypercementosis lesion development. This represents the first use of LA-ICP-MS to study the microspatial distribution of trace elements in equine teeth, establishing a baseline for elemental distribution in normal and EOTRH impacted dental hard tissue.

Quantitative fluoride imaging of teeth using CaF emission by laser induced breakdown spectroscopy.

In this work, we propose the use of molecular emission of calcium fluoride (CaF) by laser induced breakdown spectroscopy (LIBS) to obtain quantitative fluoride distribution images of teeth. LIBS has proved to be an efficient technique to detect low amounts of fluoride in solids, and human teeth have the advantage being a matrix rich in calcium. We used new calibration material from sintered hydroxyapatite pellets doped with fluoride to determine the optimized LIBS conditions of argon flow at 1 L min-1 and using the green emission bands of CaF in 530 nm, and obtained a calibration curve between 0 and 400 µg g-1, and LOD of 18 µg g-1. This methodology was applied within a rat model of fluoride exposure and showed increasing tooth-fluoride with increased exposure dose. To demonstrate applicability of this method in human teeth, we quantified fluoride distribution in teeth from three children from non-fluorinated and fluorinated water regions. Samples from children living in fluoridated water regions showed higher fluoride concentrations in dentine formed after birth, compared to a child from a non-fluoridated region. Teeth have been used as biomarkers for environmental exposure and this new method opens the opportunity in epidemiology research to study critical windows of early life exposure to fluoride as well.

Associations between Elemental Metabolic Dynamics and Default Mode Network Functional Connectivity Are Altered in Autism.

Autism is a neurodevelopmental condition associated with atypical social communication, cognitive, and sensory faculties. Recent advances in exposure biology suggest that biomarkers of elemental uptake and metabolism measured in hair samples can yield an effective signal predictive of autism diagnosis. Here, we investigated if elemental biomarkers in hair were associated with functional connectivity in regions of the default mode network (DMN) previously linked to autism. In a study sample which included twin pairs with concordant and discordant diagnoses for autism, our analysis of hair samples and neuroimaging data supported two general findings. First, independent of autism diagnosis, we found a broad pattern of association between elemental biomarkers and functional connectivity in the DMN, which primarily involved dynamics in zinc metabolism. Second, we found that associations between the DMN and elemental biomarkers, particularly involving phosphorus, calcium, manganese, and magnesium, differed significantly in autistic participants from control participants. In sum, these findings suggest that functional dynamics in elemental metabolism relate broadly to persistent patterns of functional connectivity in the DMN, and that these associations are altered in the emergence of autism.

Early life manganese exposure and reported attention-related behaviors in Italian adolescents.

Background: Manganese (Mn) is an essential nutrient and neurotoxicant, and the neurodevelopmental effects of Mn may depend on exposure timing. Less research has quantitatively compared the impact of Mn exposure on neurodevelopment across exposure periods. Methods: We used data from 125 Italian adolescents (10-14 years) from the Public Health Impact of Metals Exposure Study to estimate prospective associations of Mn in three early life exposure periods with adolescent attention-related behaviors. Mn was quantified in deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry to represent prenatal (2nd trimester-birth), postnatal (birth ~1.5 years), and childhood (~1.5-6 years) exposure. Attention-related behavior was evaluated using the Conners Behavior Rating Scales in adolescence. We used multivariable linear regression models to quantify associations between Mn in each exposure period, and multiple informant models to compare associations across exposure periods. Results: Median tooth Mn levels (normalized to calcium) were 0.4 area under the curve (AUC) 55Mn:43Ca × 104, 0.1 AUC 55Mn:43Ca × 104, and 0.0006 55Mn:43Ca for the prenatal, postnatal, and childhood periods. A doubling in prenatal tooth Mn levels was associated with 5.3% (95% confidence intervals [CI] = -10.3%, 0.0%) lower (i.e., better) teacher-reported inattention scores, whereas a doubling in postnatal tooth Mn levels was associated with 4.5% (95% CI = -9.3%, 0.6%) and 4.6% (95% CI = -9.5%, 0.6%) lower parent-reported inattention and attention deficit/hyperactivity disorder index scores, respectively. Childhood Mn was not beneficially associated with reported attention-related behaviors. Conclusion: Protective associations in the prenatal and postnatal periods suggest Mn is beneficial for attention-related behavior, but not in the childhood period.

Elemental Dynamics in Hair Accurately Predict Future Autism Spectrum Disorder Diagnosis: An International Multi-Center Study.

Autism spectrum disorder (ASD) is a neurodevelopmental condition diagnosed in approximately 2% of children. Reliance on the emergence of clinically observable behavioral patterns only delays the mean age of diagnosis to approximately 4 years. However, neural pathways critical to language and social functions develop during infancy, and current diagnostic protocols miss the age when therapy would be most effective. We developed non-invasive ASD biomarkers using mass spectrometry analyses of elemental metabolism in single hair strands, coupled with machine learning. We undertook a national prospective study in Japan, where hair samples were collected at 1 month and clinical diagnosis was undertaken at 4 years. Next, we analyzed a national sample of Swedish twins and, in our third study, participants from a specialist ASD center in the US. In a blinded analysis, a predictive algorithm detected ASD risk as early as 1 month with 96.4% sensitivity, 75.4% specificity, and 81.4% accuracy (n = 486; 175 cases). These findings emphasize that the dynamics in elemental metabolism are systemically dysregulated in autism, and these signatures can be detected and leveraged in hair samples to predict the emergence of ASD as early as 1 month of age.

Air Pollution and Maximum Temperature Are Associated with Neurodevelopmental Regressive Events in Autism Spectrum Disorder.

Neurodevelopmental regression (NDR) is an enigmatic event associated with autism spectrum disorder (ASD) during which a child loses previously acquired skills and develops ASD symptoms. In some, a trigger which precedes the NDR event, such as a fever, can be identified, but in many cases no trigger is obvious. We hypothesize that air pollution (PM2.5) may trigger NDR, especially in those children without an identified trigger. Average daily PM2.5, ozone, precipitation and maximum temperature (Tmax) were derived from Environmental Protection Agency models and National Oceanic and Atmospheric Administration monitors based on zip-code information from 83 ASD participants during the six-weeks following the onset month of an NDR event and a reference period defined as one year before and one year after the event. Seasonally adjusted logistic regression (LR) and linear mixed models (LMM) compared cases (with a history of NDR) and matched controls (without a history of NDR). LR models found that the risk of NDR was related to higher PM2.5 during 3 to 6 weeks of the NDR event period, particularly in those without a trigger. Overall, both models converged on NDR being related to a higher PM2.5 and lower Tmax both during the NDR event period as well as the reference period, particularly in those without a known trigger. This temporal pattern suggests that environmental triggers, particularly PM2.5, could be related to NDR, especially in those without an identifiable trigger. Further studies to determine the underlying biological mechanism of this observation could help better understand NDR and provide opportunities to prevent NDR.

Biomarkers of maternal lead exposure during pregnancy using micro-spatial child deciduous dentine measurements.

BACKGROUND: Lead is a toxic chemical of public health concern, however limited biomarkers are able to reconstruct prior lead exposures in early-life when biospecimens are not collected and stored. Although child tooth dentine measurements accurately assess past child perinatal lead exposure, it has not been established if they reflect maternal exposure in pregnancy. AIM: To assess the prenatal relationship between child tooth dentine and maternal blood lead measurements and to estimate maternal lead exposure during the 2nd and 3rd trimesters of pregnancy from weekly child dentine profiles. METHODS: We measured early-life lead exposure in child tooth dentine and maternal blood from 419 child-mother dyads enrolled in the Programming Research in Obesity, Growth, Environment and Social Stress (PROGRESS) cohort. We employed the Super-Learner algorithm to determine the relationship of dentine lead data with maternal blood lead concentrations and to predict maternal lead from child dentine lead data in blinded analyses. We validated and quantified the bias of our results internally. RESULTS: Mothers had moderate blood lead levels (trimesters: 2nd = 29.45 ug/L, 3rd = 31.78 ug/L). Trimester-averaged and weekly child dentine lead measurements were highly correlated with maternal blood levels in the corresponding trimesters. The predicted trimester-specific maternal lead levels were significantly correlated with actual measured blood values (trimesters: 2nd = 0.83; 3rd = 0.88). Biomarkers of maternal lead exposure discriminated women highly exposed to lead (>mean) with 85 % and 96 % specificity in the 2nd and 3rd trimesters, respectively, with 80 % sensitivity. DISCUSSION: Weekly child dentine lead levels can serve as biomarkers of past child and maternal lead exposures during pregnancy.

Reprint of: Elemental dysregulation in psychotic spectrum disorders: A review and research synthesis.

Accumulating evidence from observational studies, genetic research, and animal models suggests a relationship between toxic and nutritive elements and psychotic spectrum disorders (PSD). This review systematically evaluates the current research evidence for two hypotheses: 1) that exposures to abnormal levels of toxic and nutritive elements early in life contributes to the subsequent development of PSD, and 2) that an imbalance of element levels is linked to psychotic illness and clinical severity. We focused on the extant literature on five elements, lead (Pb), copper (Cu), magnesium (Mg), manganese (Mn), and zinc (Zn), because of their previously documented associations with psychiatric problems and the availability of pertinent literature. The review identified 38 studies of which 11 measured Pb, 27 measured Cu, 16 measured Mg, 15 measured Mn, and 25 measured Zn concentrations in PSD patients and controls. A majority of research has been conducted on nutritive element imbalance, and findings are largely mixed. While it is biologically plausible that element dysregulation is an important modifiable risk factor for PSD, more research into exposure in early life is needed to better characterize this relationship.

Prenatal and early childhood critical windows for the association of nephrotoxic metal and metalloid mixtures with kidney function.

INTRODUCTION: As renal development and maturation processes begin in utero and continue through early childhood, sensitive developmental periods arise during which metal exposures can program subclinical nephrotoxicity that manifests later in life. We used novel dentine biomarkers of established nephrotoxicants including arsenic (As), cadmium (Cd), lead (Pb), chromium (Cr), and lithium (Li), and their mixtures, to identify critical windows of exposure-associated kidney function alterations in preadolescents. METHODS: Participants included 353 children in the Programming Research in Obesity Growth, Environment and Social Stressors (PROGRESS) longitudinal birth cohort study based in Mexico City. Estimated glomerular filtration rate (eGFR) was assessed in 8-12 year old children using serum cystatin C measures. Pre- and postnatal metal(loid) concentrations were assessed in weekly increments by analyzing deciduous teeth with laser ablation-inductively coupled plasma-mass spectrometry. We used reverse distributed lag models (rDLMs) and lagged Weighted Quantile Sum (L-WQS) regression to examine time-varying associations between weekly perinatal metal(loid) exposure or metal(loid) mixtures and preadolescent eGFR while adjusting for age, sex, BMI z-score, SES and prenatal tobacco smoke exposure. RESULTS: We identified a critical window of susceptibility to Pb exposure, in the late 3rd trimester (5 weeks prior to birth) during which higher Pb exposure was associated with children's increased eGFR. When all elements were assessed as a mixture, we identified late 2nd/early 3rd trimester (weeks 8-17 of gestation) as a window of vulnerability associated with decreased eGFR, with Li and Cr contributing the greatest weights to the association. When stratified by sex, we observed stronger effects among boys than girls. CONCLUSIONS: Using tooth-matrix biomarkers, we identified discrete developmental exposure windows wherein Pb and metal(loid) mixtures were associated with altered preadolescent kidney function.